Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroendocrine axes function as an ensemble of regulatory loci which communicate and maintain homeostasis via time-delayed blood-borne signals. The growth hormone (GH)-insulin-like growth factor I (IGF-I) feedback axis sustains a vividly pulsatile mode of interglandular signalling. Pulsatility is driven jointly by hypothalamic GH-releasing hormone (GHRH) and GH-releasing peptide (GHRP), and modulated by somatostatinergic restraint. Paradoxically, intermittent somatostatin inputs also facilitate somatotrope-cell responses to recurrent secretagogue stimuli, thereby amplifying pulsatile GH secretion. A concurrent low basal (8-12% of normal total) rate of GH release is controlled positively by GHRH and GHRP and negatively by somatostatin. Sex-steroid hormones (such as oestradiol and aromatizable androgen) and normal female and male puberty augment GH secretory-burst mass 1.8- to 3.5-fold, whereas ageing, relative obesity, physical inactivity, hypogonadism, and hypopituitarism mute the amplitude/mass of pulsatile GH output. An abrupt rise in circulating GH concentration stimulates rapid internalization of the GH receptor in peripheral target tissues, and evokes second-messenger nuclear signalling via the STAT 5b pathway. Discrete GH peaks stimulate linear (skeletal) growth and drive muscle IGF-I gene expression more effectually than basal (time-invariant) GH exposure. A brief pulse of GH can saturate the plasma GH-binding protein system and achieve prolonged plasma GH concentrations by convolution with peripheral distribution and clearance mechanisms. A single burst of GH secretion also feeds back after a short latency on central nervous system (CNS) regulatory centres via specific brain GH receptors to activate somatostatinergic and reciprocally subdue GHRH outflow. This autoregulatory loop probably contributes to the time-dependent physiologically pulsatile dynamics of the GH axis. More slowly varying systemic IGF-I concentrations may also damp GH secretory pulse amplitude by delayed negative-feedback actions. According to this simplified construct, GH pulsatility emerges due to time-ordered multivalent interfaces among GHRH/GHRP feedforward and somatostatin, GH and IGF-I feedback signals. Resultant GH pulses trigger tissue-specific gene expression, thereby promoting skeletal and muscular growth, metabolic and body compositional adaptations, and CNS reactions that jointly maintain health and homeostasis.
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PMID:Neurophysiological regulation and target-tissue impact of the pulsatile mode of growth hormone secretion in the human. 1152 85

Decidualization of endometrial stromal cells is a prerequisite for human implantation and occurs in vivo in response to progesterone and involves activation of the protein kinase A (PKA) pathway. The objective of this study was to determine the molecular signatures and patterns of gene expression during stimulation of this pathway with an analog of cAMP. Endometrial stromal cells from two subjects were treated with or without 8-Br-cAMP (1 mM) for 0, 2, 12, 24, 36, and 48 h and were processed for microarray analysis, screening for 12,686 genes and ESTs. Most abundantly upregulated genes included neuropeptides, immune genes, IGF family members, cell cycle regulators, extracellular matrix proteases, cholesterol trafficking, cell growth and differentiation, hormone signaling, and signal transduction. Most abundantly downregulated genes included activator of NF-kappaB, actin/tropomyosin/calmodulin binding protein, cyclin B, IGFBP-5, alpha1 type XVI collagen, lipocortin III, l-kynurenine hydrolase, frizzle-related protein, and cyclin E2. RT-PCR validated upregulation of IGFBP-1, preprosomatostatin, and IL-11, and Northern analysis validated their kinetic upregulation. RT-PCR confirmed downregulation of IGFBP-5, cyclin B, and TIL-4. K-means analysis revealed four major patterns of up- and downregulated genes, and genes within each ontological group were categorized into these four kinetic patterns. Within each ontological group different patterns of temporal gene expression were observed, indicating that even genes within one functional category are regulated differently during activation of the PKA pathway in human endometrial stromal cells. Overall, the data demonstrate kinetic reprogramming of genes within specific functional groups and changes in genes associated with nucleic acid binding, cell proliferation, decreased G protein signaling, increased STAT pathway signaling, structural proteins, cellular differentiation, and secretory processes. These changes are consistent with cAMP modulating early events (0-6 h) primarily involving cell cycle regulation, subsequent events (12-24 h) involving cellular differentiation (including changes in morphology and secretory phenotype), and late events (24-48 h) mediating more specialized function, including immune modulators, in the human endometrial stromal cell.
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PMID:Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation. 1453 34

The pancreatic beta-cell plays a central role in the maintenance of glucose homeostasis and in the pathogenesis of both type 1 and type 2 diabetes mellitus. Elucidation of the insulin secretory defects observed in diabetes first requires a better understanding of the complex mechanisms regulating insulin secretion, which are only partly understood. While there have been reports detailing proteomic analyses of islet cell lines or isolated rodent islets, the information gained is not always applicable to humans. Therefore, definition of the human islet proteome could contribute to a better understanding of islet biology and lead to more effective treatment strategies. We have applied a two-dimensional LC-MS/MS-based analysis to the characterization of the human islet proteome, resulting in the confident identification of 29,021 different tryptic peptides covering 3365 proteins (> or =2 unique peptide identifications per protein). As expected, the three major islet hormones (insulin, glucagon, and somatostatin) were detected, as well as various beta-cell enriched secretory products, ion channels, and transcription factors. In addition, significant proteome coverage of metabolic enzymes and cellular pathways was observed, including the integrin signaling cascade and the MAP kinase, NF-kappa beta, and JAK/STAT pathways. The resulting peptide reference library provides a resource for future higher throughput and quantitative studies of islet biology.
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PMID:Characterization of the human pancreatic islet proteome by two-dimensional LC/MS/MS. 1713 36

Growth hormone (GH) acts directly at the growth plate and through the production of insulin-like growth factor (IGF)-I. At least 50% of the hormone circulates bound to GH binding protein, and its secretion is controlled by growth hormone-releasing hormone and somatostatin. Once GH binds to two GH receptors, the janus activated kinase/signal transducers and activators of transcription (JAK/STAT) protein pathway is activated, resulting in the production of IGF-I. Serum IGF-I is produced predominantly in the liver and circulates in a 140 kDa complex, along with its binding protein, IGF binding protein 3, and acid-labile protein. Recombinant human (rh) IGF-I (mecasermin) is approved by the US FDA and the European Medicines Agency for the treatment of patients with severe primary IGF deficiency or for patients with GH1 gene deletion who have developed neutralizing antibodies to GH. It has been shown to increase growth velocity in children with either condition. In the past, there have been adverse events, particularly hypoglycemia, reported with the administration of mecasermin. However, a recent report of long-term therapy with mescasermin in children with severe IGF-I deficiency has concluded that although adverse events are common, they are rarely severe enough to interrupt or modify treatment. The serum half-life of mecasermin is shorter in patients with GH insensitivity syndrome and low serum levels of its binding protein, the insulin-like growth factor binding protein (IGFBP)-3 and acid-labile subunit, compared with the serum half-life in normal volunteers or in patients with an IGF1 gene deletion who have normal levels of IGFBP-3. Mecasermin rinfabate, a complex of rhIGF-I and rhIGFBP-3, appears to prolong the serum half-life and might counteract acute adverse events, particularly hypoglycemia, associated with the administration of mescasermin. Mecasermin rinfabate, however, is no longer available in the USA or Europe for treating conditions involving short stature, because of a legal requirement. Mecasermin has been shown to be effective in increasing height velocity and adult height in patients with severe GH resistance and in IGF1 gene deletion. There has been some interest in using mecasermin to treat patients with partial GH resistance or idiopathic short stature. At the present time, the data are insufficient to make this recommendation.
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PMID:Insulin-like growth factor-I deficiency in children with growth hormone insensitivity: current and future treatment options. 1962 67